Synthesis of the Selective D2 Receptor Agonist PNU-95666E from D-Phenylalanine Using a Sequential Oxidative Cyclization Strategy

Arthur G. Romero, William H. Darlington, Moses W. McMillan

Research output: Contribution to journalArticle

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Abstract

Compound 1 (PNU-95666E) is a selective and high-affinity agonist at the dopamine D2 receptor subtype and is of interest as a potential agent for the treatment of Parkinson's disease. Requiring a synthetic route amenable to scale-up, a synthesis of this enantiomerically pure tricyclic compound was developed, starting from D-phenylalanine. Critical to the success of this synthesis were two oxidative nitrogen annulations to provide the tricyclic ring system. A highly efficient reduction with borane-methyl sulfide was used to reduce three different functional groups, a total of six hydrides transferred, with no concomitant racemization, contributing to the synthesis of 1 in eight steps with an overall yield of 26%. The utility of this synthetic route has been demonstrated by the completion this synthesis on multikilogram scale.

Original languageEnglish
Pages (from-to)6582-6587
Number of pages6
JournalJournal of Organic Chemistry
Volume62
Issue number19
StatePublished - Dec 1 1997
Externally publishedYes

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